A tumor-targeting porphyrin-micelle with enhanced STING agonist delivery and synergistic photo-/immuno- therapy for cancer treatment

The activation of STING pathway has emerged as a promising strategy in cancer immunotherapy. However, challenges associated with unfavorable physicochemical properties and potential off-target toxicities have limited the application of STING agonists. Here, we develop an amphiphilic and cationic charged porphyrinpolymer to electrostatically load the STING agonist (MSA-2) within a micellar structure, thereby enhancing carrier compatibility and drug-loading content of MSA-2. Additionally, tumor-targeting ligands were functionalized onto the micelle to enhance specificity for tumor cells, aiming to significantly improve tumor accumulation while minimizing undesirable toxicity. The resultant tumor-targeting porphyrin micelle (TPC@M) seamlessly integrates three therapeutic mechanisms: i) tumor ablation via phototherapy; ii) robust activation of the STING pathway by MSA-2; iii) synergistic photo-/immuno- stimulations. TPC@M efficiently ablates primary tumors through phototherapy and further activates adaptive immune responses synergistically with MSA-2induced innate immunity to suppress metastasis and prevent recurrence. Overall, we transformed a deliverycompromised therapeutic into a precise, stable, and safe nanomedicine that unleashes synergistic immunotherapeutic effects. Statement of significance: This study addresses the urgent need for an efficient delivery system to fully harness the potential of the STING agonist MSA-2 in cancer immunotherapy. The cGAS-STING pathway plays a critical role in modulating anti-tumor immunity; however, the clinical application of MSA-2 has been hindered by its poor physicochemical properties and off-target effects. Our innovative approach introduces a tumor-targeting porphyrin-based polymeric micelle (TPC@M) that efficiently encapsulates MSA-2, overcoming compatibility issues associated with traditional nanocarriers. The TPC@M not only exhibits enhanced tumor targeting and reduced toxicity but also integrates phototherapy with immunotherapy, providing a synergistic strategy for cancer treatment. Our in vivo findings using 4T1 breast cancer mouse models demonstrate significant inhibition of tumor growth and prevention of metastasis, accompanied by a robust and long-lasting immune response.